Bruton's tyrosine kinase (abbreviated below as “Btk”) belongs to the Tec family of kinases, which are non-receptor tyrosine kinases, and is selectively expressed in the B cell and myelocyte lines. Btk plays an important role in signal transduction in B cells and is a factor that contributes to the survival, differentiation, proliferation, and activation of B cells. Signaling in B cells via the B cell antigen receptor (BCR) induces a broad range of biological responses, and abnormal signal transduction here causes abnormal B cell activation and the formation of pathogenic autoantibodies. Btk is believed to form a link in the BCR-mediated signal transduction pathways into B cells. Thus, X-linked agammaglobulinemia (XLA) is known to be caused by a defect in the human Btk gene that results in the induction of abnormal B cell differentiation and a drastic decline in immunoglobulin production (refer to Non-patent Document 1). The symptoms of this disease include a substantial decline in B cells in the peripheral blood and an increased susceptibility to bacterial infections. Btk is also known to participate in mast cell activation and in the physiological functions of platelets. Due to this, compounds that have a Btk inhibitory activity are effective for the treatment of diseases in which B cells or mast cells participate, for example, allergic diseases, autoimmune diseases, inflammatory diseases, thromboembolic diseases, and cancers (refer to Non-patent Document 2).
The following compounds are known as prior art for the compounds of the present invention.
Compounds represented by general formula (A) are known as compounds that have a Btk inhibitory activity
[C 2]
(in the formula, LaA represents CH2, O, NH, or S; ArA represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; YA represents any substituent selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; ZA represents CO, OCO, NHCO, or CS; R7-A and R8-A each independently represent H, unsubstituted C1-C4 alkyl, substituted C1-C4 alkyl, unsubstituted C1-C4 heteroalkyl, substituted C1-C4 heteroalkyl, unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, unsubstituted C2-C6 heterocycloalkyl, and substituted C2-C6 heterocycloalkyl; or R7-A and R8-A together form a bond; and R6-A represents H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 heteroalkyl, C1-C6 alkoxyalkyl, C1-C8 alkylaminoalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted aryl (the definitions of these groups have been excerpted)) (refer to Patent Documents 1, 2, and 3).
On the other hand, for example, compounds represented by general formula (B)
[C 3]
(in the formula, Q1B and Q2B are independently selected from CX1B, CX2B, and nitrogen; Q3B represents N or CH; X1B and X2B are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, cyano, halogen, and so forth; R1B is selected from the group consisting of hydrogen and (C1-C6) alkyl; yB represents 0 or an integer from 1 to 3; R2B and R3B are independently selected from hydrogen and (C1-C6) alkyl; R4B is selected from the group consisting of alkyl, heterocyclyl, aryl, heteroaryl, and so forth; and R5B is selected from the group consisting of alkyl, heterocyclyl, and substituted heterocyclyl (the definitions of these groups have been excerpted)) (refer to Patent Document 4) are known as compounds that have a purinone skeleton.
Compounds represented by general formula (C) are also known
[C 4]
(in the formula, XC is selected from the group consisting of nitrogen and CR8C; R8C is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, and so forth; Q1C is selected from the group consisting of O, S, and so forth; ZC is selected from the group consisting of oxygen, sulfur, and NY5C; Y5C is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, and so forth; Q2C, Q3C, and Q4C are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and so forth; R2C is selected from the group consisting of hydrogen and substituted or unsubstituted alkyl; and nC represents 0, 1, 2, 3, or 4 (the definitions of these groups have been excerpted)) (refer to Patent Document 5).
Compounds having a purinone skeleton are also disclosed as formula 20 (refer to paragraph number 0028) in Patent Document 6.
Compounds represented by general formula (D) are also known
[C 5]
(in the formula, R1D represents a group selected from hydrogen, substituted or unsubstituted alkyl,[C 6]
and so forth; R2D represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; YD represents a group selected from O, C—NO2, and S; ZD represents a group selected from[C 7]
and so forth; here, AD, DD, ED, and MD each independently represent CR12D, N, and N-oxide; R12D represents a group selected from hydrogen, halogen, amino, hydroxy, and cyano; XD represents a group selected from O, C—NO2, and S; R6D represents a group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted aryl; the indication aD represented by the dashed line represents a single bond or a double bond; and nD represents an integer selected from 0, 1, and 2) (refer to Patent Document 7).
The compounds of the present invention are compounds that, in addition to having a Btk-selective inhibitory activity, exhibit an excellent metabolic stability and can avoid a CYP inhibitory activity and adverse reactions such as, for example, hepatotoxicity; however, there is no statement or suggestion relating to these characteristic features in any of the prior art documents.    Patent Document 1: Japanese Translation of PCT Application No. 2010-504324    Patent Document 2: WO 2008/121742    Patent Document 3: WO 2010/009342    Patent Document 4: WO 2008/060301    Patent Document 5: WO 2007/142755    Patent Document 6: Japanese Translation of PCT Application No. 2003-509427    Patent Document 7: WO 2003/037890    Non-patent Document 1: Nature, Volume 361, pp. 226-233, 1993    Non-patent Document 2: Anticancer Agents in Medicinal Chemistry, Volume 7, Number 6, pp. 624-632, 2007